Oncotarget

Research Papers:

EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions

Mohammad Alzrigat _, Alba Atienza Párraga, Prasoon Agarwal, Hadil Zureigat, Anders Österborg, Hareth Nahi, Anqi Ma, Jian Jin, Kenneth Nilsson, Fredrik Öberg, Antonia Kalushkova, Helena Jernberg-Wiklund

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Abstract

Mohammad Alzrigat1, Alba Atienza Párraga1,*, Prasoon Agarwal2,*, Hadil Zureigat3, Anders Österborg4, Hareth Nahi5, Anqi Ma6, Jian Jin6, Kenneth Nilsson1, Fredrik Öberg1, Antonia Kalushkova1, Helena Jernberg-Wiklund1

1Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden

2Department of Laboratory Medicine, Division of Clinical Immunology, Karolinska University Hospital, Huddinge, Stockholm, Sweden

3Department of Medicine, Faculty of Medicine, University of Jordan, Amman, Jordan

4Department of Oncology-Pathology, Karolinska University Hospital, Solna, Stockholm, Sweden

5Department of Medicine, Unit of Hematology, Karolinska University Hospital, Huddinge, Stockholm, Sweden

6Department of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

*These authors have contributed equally to this work

Correspondence to:

Helena Jernberg-Wiklund, email: helena.jernberg_wiklund@igp.uu.se

Mohammad Alzrigat, email: mohammad.alzrigat@igp.uu.se

Keywords: multiple myeloma, EZH2, H3K27me3, microRNA, UNC1999

Received: October 09, 2016    Accepted: December 15, 2016    Published: December 30, 2016

ABSTRACT

Multiple Myeloma (MM) is a plasma cell tumor localized to the bone marrow (BM). Despite the fact that current treatment strategies have improved patients' median survival time, MM remains incurable. Epigenetic aberrations are emerging as important players in tumorigenesis making them attractive targets for therapy in cancer including MM. Recently, we suggested the polycomb repressive complex 2 (PRC2) as a common denominator of gene silencing in MM and presented the PRC2 enzymatic subunit enhancer of zeste homolog 2 (EZH2) as a potential therapeutic target in MM. Here we further dissect the anti-myeloma mechanisms mediated by EZH2 inhibition and show that pharmacological inhibition of EZH2 reduces the expression of MM-associated oncogenes; IRF-4, XBP-1, PRDM1/BLIMP-1 and c-MYC. We show that EZH2 inhibition reactivates the expression of microRNAs with tumor suppressor functions predicted to target MM-associated oncogenes; primarily miR-125a-3p and miR-320c. ChIP analysis reveals that miR-125a-3p and miR-320c are targets of EZH2 and H3K27me3 in MM cell lines and primary cells. Our results further highlight that polycomb-mediated silencing in MM includes microRNAs with tumor suppressor activity. This novel role strengthens the oncogenic features of EZH2 and its potential as a therapeutic target in MM.

Author Information

Mohammad Alzrigat
Primary Contact  _

Alba Atienza Párraga

Prasoon Agarwal

Hadil Zureigat

Anders Österborg

Hareth Nahi

Anqi Ma

Jian Jin

Kenneth Nilsson

Fredrik Öberg

Antonia Kalushkova

Helena Jernberg-Wiklund


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